tbuckley/cabot-search huggingface dataset:
Physicians’ acceptance of extended or intermittent adjuvant endocrine therapy (AET): A survey on breast cancer (BC) physicians.
Authors: Louis Wing-Cheong Chow
Journal: Journal of Clinical Oncology (2022)

e12515 Background: The results from the GIM4, SALSA, and SOLE trials are potentially practice-changing, but it was unknown whether physicians would accept these trial results and adjust their AET prescriptions for postmenopausal women with BC. Methods: A cross-sectional survey involving 77 BC physicians in China was conducted. The survey questions were developed based on the GIM4, SALSA, and SOLE trial results, as well as referred to the latest NCCN guidelines. Statistical analyses were performed using SPSS version 28.0. Results: Almost half (48%) of the respondents were breast surgeons, 19% were breast specialists, 8% were medical oncologists, and 2% were general surgeons. Forty-five percent of the respondents had a clinical experience of ≥15 years, and the mean ± SD number of BC patients managed annually was 762.10 ± 1,254.50. For pN0, tumor size ≤0.5cm, postmenopausal patients, respondents with ≥15 years of clinical experience were more likely to prescribe a longer duration of AET as compared to those with &lt;15 of clinical experience (p=0.025 and p=0.038 for patients receiving prior 4-5 years of tamoxifen [TAM] and prior 5 years of aromatase inhibitor [AI], respectively). More than half (57.1%) did not agree with the hypothesis that AI resistance can be reversed by intermittent letrozole treatment (the SOLE trial hypothesis), but 50.6% considered intermittent letrozole as an acceptable option, especially for patients with ≤3 positive nodes (79.5%), tumor grade 1 (84.6%), tumor size ≤2cm (82.1%), HER2 negative disease (74.4%). Conclusions: A high proportion of the BC physician respondents would prescribe extended AET with AI beyond 5 years for postmenopausal women with BC, especially for those with higher risk. Intermittent letrozole was considered as an acceptable option for low-risk patients.[Table: see text]
The role of an alpha-selective phosphoinositide-3 kinase inhibitor in vascular inflammation
Authors: H Chaudhry, A Zarban, X Kodji, C Cerutti, F Argunhan, A Ridley, SD Brain
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): British Heart Foundation Introduction Cardiovascular inflammation is associated with endothelial cell (EC) damage, resulting in leukocyte trafficking and oedema formation. Inflammation disrupts EC junctions, increasing microvascular permeability, and resulting in a positive-feedback loop of inflammatory events. The phosphoinositide 3-kinase pathway stimulates this endothelial response and this study examined the actions of BYL-719, a PI3K-α selective inhibitor, on inflammatory responses. Method Confocal imaging using immunofluorescence and permeability assays were undertaken to quantify the effect of inflammatory cytokines, TNF-α and IL-1β, in the presence of the PI3K inhibitor using fluorescein isothiocyanate-dextran (40 kDa, 0.1 mg/ml) on human microvascular endothelial cells (HMVEC) (Lonza, derived from dermal tissue). Cells were treated with either cytokine for 16-18 h, followed by a 1 h treatment of drug and a final 1 h treatment with FITC-dextran. In vivo analysis was carried out per the UK Home Office Animals (Scientific Procedures) Act 1986. Male WT CD1 mice were anaesthetised initially using 5% isoflurane and maintained at 2% for procedures, to test BYL-719 in a model of dorsal skin inflammation, to determine neutrophil accumulation (measured by myeloperoxidase) and oedema formation (measured by Evans Blue accumulation). All statistical significance was determined using one-way or two-way ANOVA followed by Tukey’s post hoc test. Results BYL-719 significantly reduced cytokine-induced EC permeability and shape changes, including cell area and elongation (Table 1), impeding in vitro cytokine-induced inflammation. The inhibitor, abrogated effects of the inflammatory cytokines in vivo of both TNF-α and IL-1β, but interestingly had no effect on the neutrophil accumulation or oedema formation in the presence of C5a (Figure 1). Figure 1: The effect of BYL-719 in the dorsal skin inflammation model. Mice were pre-treated with 50 mg/kg BYL-719 intraperitoneally for 30 min, injected intravenously with Evans Blue dye, intradermally injected with TNF-α (100ng/50ul), IL-1β (10ng/50ul) and C5a (300ng/50ul) for 4 h, followed by ex vivo MPO assay (A) and oedema volume measurements (B). Data are mean ±SEM two-way ANOVA by Tukey test., n=6 independent experiments in duplicates; p* &amp;lt; 0.05 and p**** &amp;lt; 0.0001 between control (DMSO) and BYL-719 treated groups. Conclusions Our findings show that the PI3K-α inhibitor, BYL-719, reduces endothelial activation and inhibits inflammatory oedema formation in the presence of TNF-α and IL-1β. We conclude that there is a potential for PI3K inhibitors to act as anti-neutrophil and oedema agents in cardiovascular-related inflammatory conditions.
IMMU-03. Synergy between TMZ and individualized multimodal immunotherapy to improve Overall Survival of IDH1 wild-type MGMT promoter-unmethylated GBM patients
Authors: Stefaan Van Gool, Jennifer Makalowski, Michael Bitar, Peter Van de Vliet, Volker Schirrmacher, Wilfried Stuecker
Journal: Neuro-Oncology (2022)

Abstract The prognosis of IDH1 wild-type MGMT promoter-unmethylated GBM patients remains poor. Addition of Temozolomide (TMZ) to first-line local treatment shifted the median overall survival (OS) from 11.8 to 12.6 months. We retrospectively analysed the value of individualized multimodal immunotherapy (IMI) to improve OS in these patients. All adults meeting the criteria and treated 06/2015-06/2021 were selected. Thirty-two patients (12f, 20m) had a median age of 47y (range 18-69) and a KPI of 70 (50-100). Extent of resection was complete (11), &amp;lt;complete (12) or not documented (9). Seven patients were treated with surgery/radio(chemo)therapy and subsequent IMI (Group-1); 25 patients were treated with radiochemotherapy followed by maintenance TMZ plus IMI during and after TMZ (Group-2). Age, KPI and extent of resection were not different amongst both groups. The median OS of group-1 patients was 11m (2y OS: 0%). Surprisingly the median OS of group-2 patients was 22m with 2y OS of 36% (CI95%: 16-57), which was significantly (Log-rank: p = 0.0001) different from group-1. The data suggest that addition of IMI after local therapy on its own has no relevant effect on OS in these GBM patients, similar to maintenance TMZ. However, the combination of both TMZ + IMI significantly improved OS. This finding might also have implications in the search for novel combined treatment approaches for children with malignant glioma.
Correction: Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor–Resistant, <i>EGFR</i>-Mutated Non–Small Cell Lung Cancer
Journal: Cancer Discovery (2022)

In Table 1 in the original version of this article (1), the value in row “Ex19ins” and column “Pooled RDE” should be “1 (2).” Table 1 has been corrected in the latest online HTML and PDF versions of the article. The authors regret the error.
DIPG-33. Treating Pediatric Diffuse Intrinsic Pontine Glioma with Brain Radiation and Temozolomide: A Case Report
Authors: Diko Anugrah Ramadhan, Wanda Gautami, Ludi Dhyani Rahmartani, Achmad Rafli, Handoko Handoko, Endang Nuryadi, Mohamad Yanuar Amal
Journal: Neuro-Oncology (2022)

Abstract Diffuse Intrinsic Pontine Gliomas (DIPG) is a rare and highly aggressive central nervous system tumour arising from glial cells which occur mostly in children. It remains a potentially deadly cancer despite treatment, with the highest mortality rate, in which most children die within 1-year of diagnosis. Radiation therapy might improve the clinical symptoms, but the results are temporary, with tumor progression typically occurring months post radiation, whereas chemotherapy remains controversial. Here we present a case report of a patient with DIPG Indonesia and how we diagnose and currently treat it. An eight years-old boy presented with decrease level of consciousness with headache, limb weakness, slurred speech, double vision, hemifacial weakness, paraplegia, and disequilibrium which worsened two weeks prior to admission. He was initially noted to have a medially inverted left eye two months prior to admission. On physical examination, there was a N.VI and N.VII palsy, hyperreflexia, paraplegia, and nystagmus. Head MRI demonstrated a solid with minimal enhancement after contrast administration in the left pons region extending into mesencephalon with cystic component and flat floor of fourth ventricle sign, causing hydrocephalus, suggestive diffuse intrinsic pontine glioma. He was given fractionated focal intensity modulated radiation therapy (IMRT) to the tumor along with 5 mm margins with a total dose of 54 Gy. 1.8 Gy fractions, given once daily for 5 days per week over a period of 6 weeks. Supportive care in the form of corticosteroids is used to treat the peri-tumoral edema. There was a short period of motoric improvement. But then the disease progressed with the latest head CT showed hydrocephalus formation with increased size of mass. He is treated with chemotherapy using Temozolomide, and currently alive after 3 months post diagnosis. Keywords: childhood brain tumour, Diffuse Intrinsic Pontine Glioma, radiation therapy
Strokes of a pen: seeing far beyond COVID-19
Authors: Massimiliano Polastri, Salvatore Campanello
Journal: European Respiratory Journal (2022)

<b>COVID-19 has monopolised attention. However, we must not forget other severe pulmonary pathologies. This editorial illustrates three drawings with lung disease as their subject and the perceptions they transmit.</b>https://bit.ly/3sQU54Q
Lymph node staging with 18F-PSMA-1007 PET/CT in newly diagnosed prostate cancer using histopathological evaluation as a reference
Authors: R. Hermsen, E.B.C. Wedick, M.J.M. Vinken, L.W.M. Van Kalmthout, H.V.N. Küsters-Vandevelde, C.H.W. Wijers, D.M. Somford, J-P.A. Van Basten
Journal: European Urology (2022)
Animal Models of Dysregulated Cardiac Metabolism
Authors: Heiko Bugger, Nikole J. Byrne, E. Dale Abel
Journal: Circulation Research (2022)

As a muscular pump that contracts incessantly throughout life, the heart must constantly generate cellular energy to support contractile function and fuel ionic pumps to maintain electrical homeostasis. Thus, mitochondrial metabolism of multiple metabolic substrates such as fatty acids, glucose, ketones, and lactate is essential to ensuring an uninterrupted supply of ATP. Multiple metabolic pathways converge to maintain myocardial energy homeostasis. The regulation of these cardiac metabolic pathways has been intensely studied for many decades. Rapid adaptation of these pathways is essential for mediating the myocardial adaptation to stress, and dysregulation of these pathways contributes to myocardial pathophysiology as occurs in heart failure and in metabolic disorders such as diabetes. The regulation of these pathways reflects the complex interactions of cell-specific regulatory pathways, neurohumoral signals, and changes in substrate availability in the circulation. Significant advances have been made in the ability to study metabolic regulation in the heart, and animal models have played a central role in contributing to this knowledge. This review will summarize metabolic pathways in the heart and describe their contribution to maintaining myocardial contractile function in health and disease. The review will summarize lessons learned from animal models with altered systemic metabolism and those in which specific metabolic regulatory pathways have been genetically altered within the heart. The relationship between intrinsic and extrinsic regulators of cardiac metabolism and the pathophysiology of heart failure and how these have been informed by animal models will be discussed.
Risk of adverse outcomes after prostatectomy in patients diagnosed with IUSP &lt;= 2 prostate cancer on MRI/TRUS fusion biopsy
Authors: C.V. Kesch, V. Pantea, T. Soeterik, A. Marquis, G. La Bombarda, A. Morlacco, F. Barletta, F. Preisser, F. Zattoni, G. Marra, R.C.N. Van Den Bergh, J.P. Radtke, B.A. Hadaschik, G. Gandaglia
Journal: European Urology (2022)
Dexamethasone should not be given to people with a chronic subdural haematoma
Authors: Helen Saul, Deniz Gursul, Samantha Cassidy, Peter Hutchinson, Angelos Kolias
Journal: BMJ (2022)

The studyHutchinson P, Edlmann E, Bulters D, et al. Trial of dexamethasone for chronic subdural haematoma. N Engl J Med 2020;383:2616-27.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/dexamethasone-should-not-be-used-chronic-subdural-haematoma/.
The combination timing of radio-immunotherapy determines immune microenvironment remodeling and abscopal effect through eosinophils.
Authors: Xiaoxia Zhu, Shangbiao Li
Journal: Journal of Clinical Oncology (2022)

e14566 Background: Recently, several studies have confirmed the abscopal effect of tumor shrinkage outside the irradiated field induced by local radiotherapy (RT) combined with immunotherapy. The timing of the combination, including concurrent and sequential treatment, may affect the anti-tumor efficacy of radiotherapy and immune checkpoint inhibitors (ICIs). However, the optimal timing of RT combined with immunotherapy to enhance the abscopal effect and the underlying mechanism are still unknown. Methods: The animal model of bilateral subcutaneous tumor of MC38 in C57BL/6J mice were randomly divided into four groups: PD-1 therapy (P1) group, radiotherapy (unilateral irradiation, 8Gy × 3F, the same below) concurrent with anti-PD-1 therapy (Con.) group, anti-PD-1 therapy one week after radiotherapy (Seq.1) group and anti-PD-1 therapy two weeks after radiotherapy (Seq.2) group. RNA sequencing was employed to identify differential genes. The changes of the immune microenvironment of tumor-draining lymph nodes (TDLN) and tumors were detected by flow cytometry. The expression of chemokine receptors, ligands, and cytokines was detected by qPCR, western blot, and ELISA. Results: The results showed that the survival benefit of sequential PD-1 inhibitor after RT was higher than that of the Con. group and P1 group., the survival benefited most in Seq.1 group, particularly. Similarly, tumor growth on both sides was significantly inhibited in Seq.1 group compared with the Con. group, P1 group, and Seq2. group. Furthermore, a combination of RT with anti-PD-1 inhibitor induced changes of immune microenvironment in irradiated tumor, abscopal tumor and TDLN. In the Seq.1 group, the tumor immune microenvironment was reshaped, including increased eosinophils and CD8+T cells infiltration, while decreased Treg, MDSCs, and TAMs frequency. Correspondingly, the expression of crucial chemokine receptors and ligands involved in chemotaxis of eosinophils and CTL CD8+T cells was up-regulated in tumors of mice in the Seq.1 group. After eosinophil neutralization in vivo, the survival of mice in Seq.1 group was significantly shortened. Besides, the anti-tumor effect and abscopal effect were significantly weakened, accompanied by deduction of the infiltration of T cells, especially cytotoxicity CD8+T cells in the immune microenvironment. Conclusions: Our results showed that RT combined with PD-1 inhibitors could induce a synergistic anti-tumor effect. Sequential PD-1 inhibitor one week after RT could enhance the anti-tumor effect most, including the abscopal effect. The mechanism related to eosinophils recruitment, which established a tumor-suppressive immune microenvironment mainly through enrichment of anticancer T lymphocytes in abscopal tumors. This study provides an insight for clinical precision treatment in combination of RT and immunotherapy.
Conviction Narrative Theory: A theory of choice under radical uncertainty
Authors: Samuel G. B. Johnson, Avri Bilovich, David Tuckett
Journal: Behavioral and Brain Sciences (2022)

Conviction Narrative Theory (CNT) is a theory of choice under radical uncertainty - situations where outcomes cannot be enumerated and probabilities cannot be assigned. Whereas most theories of choice assume that people rely on (potentially biased) probabilistic judgments, such theories cannot account for adaptive decision-making when probabilities cannot be assigned. CNT proposes that people use narratives - structured representations of causal, temporal, analogical, and valence relationships - rather than probabilities, as the currency of thought that unifies our sense-making and decision-making faculties. According to CNT, narratives arise from the interplay between individual cognition and the social environment, with reasoners adopting a narrative that feels "right" to explain the available data; using that narrative to imagine plausible futures; and affectively evaluating those imagined futures to make a choice. Evidence from many areas of the cognitive, behavioral, and social sciences supports this basic model, including lab experiments, interview studies, and econometric analyses. We identify 12 propositions to explain how the mental representations (narratives) interact with four inter-related processes (explanation, simulation, affective evaluation, and communication), examining the theoretical and empirical basis for each. We conclude by discussing how CNT can provide a common vocabulary for researchers studying everyday choices across areas of the decision sciences.
Brain metastasis as first and only metastatic relapse site portends poor outcomes in patients with advanced HER2+ breast cancer.
Authors: Laura Noteware, Gloria Broadwater, Nicole Dalal, Laura Alder, James Emmett Herndon, Scott R. Floyd, Amanda E.D. Van Swearingen, Carey K. Anders, Sarah Sammons
Journal: Journal of Clinical Oncology (2022)

1045 Background: In patients (pts) with stable or no extracranial disease (ECD) presenting with breast cancer brain metastases (BCBrMs), current guidelines recommend pts receive local therapy with radiation +/- surgery, without changing systemic therapy. However, preliminary studies suggest that pts with isolated HER2+ BCBrM without ECD have inferior overall survival (OS) compared to pts with concurrent ECD. Our study further explores the implications of ECD status on intracranial progression free survival (iPFS) and OS. Methods: Retrospective analysis was performed on data from 153 pts diagnosed with initial HER2+ BCBrM who received CNS radiation at Duke between 2008 and 2020. Demographics, dates of metastatic and BCBrM diagnosis, ECD status at first CNS event, systemic therapy, and outcomes were collected. The primary endpoint was iPFS defined as the time from first CNS radiation to the subsequent documentation of intracranial progression (RANO-BM). OS was defined as time from first CNS radiation and first metastatic disease to date of death or last known contact. ECD status was defined by RECIST1.1 from systemic staging scans within 30 days of first CNS event. Results: In this cohort of 153 pts with HER2+ BCBrMs undergoing CNS radiation, &gt; 70% of pts with known ECD status had controlled systemic disease: either no ECD (27%) or stable/responding disease (44%). 64% of pts’ tumors were ER+. Median age was 50 years (range 24 – 75). Most pts (59%) developed first CNS event during adjuvant or 1 st /2 nd line metastatic therapy. CNS radiation treatment included 48% of pts receiving SRS only, 9% WBRT only, and 43% SRS and WBRT. All pts with no ECD presented with isolated BCBrMs as first metastatic disease. Among pts with known ECD status, OS from initial metastatic disease to death was markedly worse for pts with isolated brain metastases or no ECD (median = 28.4m, 95% CI: 18.1 to not reached) compared to those with progressive or stable/responding ECD (48.8m, 95% CI: 40.5 to 65.0; and 68.1m, 95% CI: 55.2 to 85.7, respectively; log-rank p = 0.004). OS from first CNS involvement to death was significantly worse for pts with progressive ECD (17.8m, 95% CI: 13.7 to 28.8) versus stable/responding (36.6m, 95% CI: 29.7 to 45.2) or no ECD (28.4m, 95% CI: 18.1 to not reached; log-rank p = 0.008). iPFS did not differ statistically among subgroups of pts with known ECD status: progressive ECD (median = 7.7m), no ECD (8.3m), or stable/responding ECD (11.2m) (log-rank p = 0.15). Conclusions: Overall survival in pts with HER2+ isolated BCBrM was markedly inferior to that of pts with progressive or stable/responding ECD. Studies investigating initiation of brain penetrable HER2-targeted therapies earlier in the disease course of isolated HER2+ BCBrMs pts are warranted.
Molecular characteristics and treatment strategy in advanced, EGFR-mutant non-small cell lung cancer with concomitant BRAF variations.
Authors: Xue-Wu Wei, Jia-Yi Deng, Chongrui Xu, Zhihong Chen, Dongqin Zhu, Qian Wu, Xuchao Zhang, Yang Shao, Yi-Long Wu, Qing Zhou
Journal: Journal of Clinical Oncology (2022)

e21021 Background: BRAF variants were reported resistant mechanisms to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). However, concomitant somatic variations other than BRAF variants and efficacy of subsequent treatment remained unclear. Methods: From October 2016 to May 2020, advanced NSCLC patients who underwent next-generation sequencing and were detected with co-mutation of BRAF and EGFR activating mutations are retrospectively included. Since June 2020, EGFR-mutant patients with acquired BRAF V600E after progression from previous Osimertinib are prospectively arranged to explore efficacy of the EGFR-BRAF co-inhibition. Results: Fifty-eight patients were retrospectively identified and five patients were prospectively included. BRAF variants was acquired after a median time of 22.7 months from initial diagnosis. Variations of TP53, PIK3CA, RB1, MET, LRP1B, APC, CDKN2A, MYC, ERBB2 and SMAD4 were over 10%, which were enriched in cell cycle/p53 pathway, EGFR downstream and bypass pathway. Subsequently, median progression-free survival was 5.0 months for chemotherapy and 2.1 months for TKI treatment without targeting both EGFR and BRAF respectively (p = 0.019). Osimertinib plus vemurafenib (n = 4) or dabrafenib + trametinib (n = 1) was prospectively administrated in five patients. Median PFS was 7.8 months. Grade 3 rash was observed in one patient. Upon disease progression, activation of RAS signaling was observed. Conclusions: Variations of EGFR downstream or bypass pathway were also frequent in patient with co-mutation of EGFR and BRAF. Efficacy of subsequent TKI without targeting both EGFR and BRAF was inferior to chemotherapy. EGFR-BRAF co-inhibition showed improved efficacy. More treatment strategy should be explored in the future.
The influence of operative time and blood loss on surgical margins and functional outcomes at laparoscopic versus robotic-assisted radical prostatectomy: A prospective multicenter study
Authors: M. Maggi, D. Rosati, P. Viscuso, V. Canale, M. Frisenda, R. Catuzzi, M. Moriconi, V. Asero, E. Scarrone, A. Carbone, A.L. Pastore, A. Fuschi, G.B. Di Pierro, G.M. Busetto, E. De Berardinis, G.P. Ricciuti, V. Panebianco, F.M. Magliocca, F. Del Giudice, B.I. Chung, A. Sciarra, S. Salciccia
Journal: European Urology (2022)